This project encompasses work on diabetes and other chronic diseases based on a prospective population-based study of the Gila River Indian Community of Arizona, whose members, the Pima Indians, have the highest known prevalence and incidence of non-insulin-dependent diabetes mellitus in the world. Associations of diabetes with gene markers suggest the existence of one or more diabetes-susceptibility genes operating in the Pima population. In addition to genetic evidence, the evidence for hyperinsulinemia predicting worsening glucose tolerance, and for the intrauterine environment playing a role in the subsequent development of diabetes in the offspring, along with our previous findings of a strong relationship of obesity and diabetes development emphasize the complex set of genetic and nongenetic causes of diabetes mellitus. The findings of this project together with collaborative projects with the Phoenix Clinical Research Section, NIADDK, emphasize the importance of insulin resistance and hyperinsulinemia in the genesis of diabetes in this population. In overt diabetes, hypoinsulinemia appears to contribute to the progression of the disease. Hyperinsulinemia in Pima children may be an early abnormality (perhaps congenital and/or genetically determined) which contributes to the development of obesity and diabetes. Complications of diabetes remain an important area of study. Diabetes, especially when of long duration or requiring insulin treatment, is a strong risk factor for cataract surgery. During this year a new collaborative study on periodontal disease has been started. The magnitude of periodontal and other oral diseases will be determined and their relationships to diabetes studied. Preliminary findings suggest that periodontal disease may be another serious complication of diabetes. The effects of each disease on the management of the other will be studied. The finding that lipoprotein concentrations are different in Pimas compared with Caucasians may help in understanding differences in the incidence of macrovascular disease, a major cause of morbidity and mortality among diabetics in the general U.S. population.